Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat.
The potential effectiveness of stiripentol, a new allylic alcohol anticonvulsant, against generalized epilepsy of the absence type was evaluated in the intravenous pentylenetetrazol (PTZ) infusion seizure model in the rat. The ability of stiripentol to elevate the threshold dose of PTZ in eliciting clonic seizure (i.e., ratio of the post-drug threshold dose to the baseline threshold dose) was measured. Dose-response studies were performed after acute intraperitoneal injection and subacute oral drug treatment. Concentrations of stiripentol in plasma and whole brain were determined. Significant elevation in PTZ threshold dose was observed at a single 300 mg/kg intraperitoneal dose of stiripentol or at plasma levels exceeding 35 micrograms/ml. Maximal anticonvulsant response (i.e., a dose ratio of 3) was reached with doses at or above 450 mg/kg (or plasma concentration greater than or equal to 120 micrograms/ml), along with the appearance of neurotoxicity. Subacute treatment consisted of 9 consecutive oral doses of stiripentol over a 3 day period, until steady-state plasma stiripentol concentration was attained. Response data were obtained at dosage levels of 150, 400 and 800 mg/kg with respective mean steady-state levels of 33.2 +/- 7.8, 61.4 +/- 20.7, and 116 +/- 14 micrograms/ml. Maximal anticonvulsant effect was not reached even at the highest dose of 800 mg/kg. Correlation of threshold dose ratio with plasma and brain stiripentol concentrations showed an approximate 40% loss in anticonvulsant potency during subacute treatment. However, the animals also became more resistant to drug-induced neurotoxicity; about 40% higher plasma or brain stiripentol concentrations had to be reached for a given degree of neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Shen
D D
DD
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Levy
R H
RH
Moor
M J
MJ
Savitch
J L
JL
D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D004056:Differential Threshold; D004148:Dioxolanes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D009420:Nervous System / Q000187:drug effects; D009994:Osmolar Concentration; D010433:Pentylenetetrazole; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology*
D004148:Dioxolanes; C021092:stiripentol; D010433:Pentylenetetrazole